P667: LONG-TERM EFFICACY OF ACALABRUTINIB-BASED REGIMENS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND HIGHER-RISK GENOMIC FEATURES: POOLED ANALYSIS OF CLINICAL TRIAL DATA
Authors: M. Davids, J. Sharman, P. Ghia, J. Woyach, W. Jurczak, T. Siddiqi, P. Miranda, M. Shahkarami, T. Yu, U. Emeribe, J. Byrd
Journal: HemaSphere (2022)

Background: Chronic lymphocytic leukemia (CLL) has a highly variable disease course; patients (pts) with higher-risk genomic features typically have poor response to chemoimmunotherapy, and pts with del(17p) also have short, suboptimal response to venetoclax + obinutuzumab. Thus, novel agents such as Bruton tyrosine kinase inhibitors (BTKi), including the highly selective covalent BTKi acalabrutinib (A), are preferred treatments in this higher-risk population based on demonstrated effectiveness in higher-risk subgroups in individual studies. Aims: To assess long-term efficacy of A-based regimens in pts with treatment-naive (TN) or relapsed/refractory (R/R) CLL and higher-risk genomic features. Methods: Data were pooled from CLL pts with higher-risk genomic features treated with A ± obinutuzumab (O) in 3 clinical studies in TN CLL (ELEVATE-TN, CL-001 [TN cohort], CL-003) and 3 in R/R CLL (ASCEND, ELEVATE-RR, CL-001 [R/R cohort]). Higher risk was defined as del(17p) and/or TP53 mutation [del(17p)/TP53m], unmutated IGHV (uIGHV), or complex karyotype (CK, ≥3 chromosomal abnormalities). Efficacy analyses (progression-free survival [PFS], overall survival [OS], response rates) focus on del(17p)/TP53m and uIGHV; safety analyses also include pts with CK. Results: 801 pts (TN 313; R/R 488, median 2 prior therapy lines [range 1–10]) were included; 64 (20%) TN and 219 (45%) R/R pts had del(17p)/TP53m, among whom 44 (69%) and 170 (78%) also had uIGHV. Overall, 288 (92%) TN and 425 (87%) R/R pts had uIGHV and 47 (15%) and 160 (33%) had CK. Median pt age was 68 (TN) and 66 (R/R) y. For A-based regimens combined (A and A+O), overall response rate (ORR) was 91% (n=58/64; complete response [CR]: 20% [n=13/64]) in TN pts with del(17p)/TP53m and 96% (n=276/288; CR 16% [n=47/288) in TN pts with uIGHV. At 47.3 mo median follow-up (range 1.0–82.0), median PFS was not reached (NR) in TN pts with del(17p)/TP53m with A-based regimens; PFS rates at 48 mo suggest similar efficacy with A and A+O in TN pts with del(17p)/TP53m (76% and 77%, respectively) (Fig 1A). Median PFS was NR among TN pts with uIGHV with both A and A+O; PFS rates at 48 mo with A and A+O were 84% and 86%, respectively (Fig 1B). Median OS was NR with A and A+O in TN pts with del(17p)/TP53m or uIGHV; OS rates at 48 mo were similar for A and A+O in pts with del(17p)/TP53m (89% for both) and in pts with uIGHV (92% and 95%). In the R/R cohort (A monotherapy only), ORR was 86% (n=184/214; CR 5% [n=11/214]) in pts with del(17p)/TP53m and 87% (n=356/408; CR 7% [n=29/408]) in pts with uIGHV. At 44.0 mo median follow-up (range 0–88.0), median PFS was 38.6 mo and 46.9 mo and PFS rates at 36 mo were 54% and 65% in pts with del(17p)/TP53m and uIGHV, respectively (Fig 1C). Median OS was 60.6 mo and NR in pts with del(17p)/TP53m and uIGHV, respectively; OS rates at 36 mo were 73% and 82%. Among all higher-risk pts, incidences of grade ≥3 treatment-related AEs were 30% (TN) and 35% (R/R). Discontinuations due to treatment-related AEs occurred in 4% (TN) and 6% (R/R) of pts; 60% and 27%, respectively, remained on treatment at data cutoff. Image:Summary/Conclusion: In this pooled analysis of clinical trial data in 801 CLL pts with higher-risk genomic features, efficacy of A-based regimens led to high PFS and OS rates at a median follow-up of nearly 4 y. The safety profile in this analysis was similar to the overall safety profile of acalabrutinib. Our results demonstrate the long-term benefit of A-based regimens in CLL pts with higher-risk genomic features, regardless of line of therapy.